Functional Interaction of BRCA1 and CREBBP in Murine Hematopoiesis

Summary Both BRCA1 and CREBBP are tumor suppressor genes that are important for hematopoiesis. We have previously shown that mouse Brca1 is essential for hematopoietic stem cell (HSC) viability. In contrast to Brca1-deficiency, which results in pancytopenia, we report here that Crebbp-deficiency results in myeloproliferation associated with an increase of splenic HSCs as well as a lethal systemic inflammatory disorder (LD50=86 days). To investigate the interaction of these two proteins in hematopoiesis, we generated double Crebbp/Brca1 knock out mice (DKOs). To our surprise, DKOs had accelerated bone marrow failure compared to Brca1-deficienct mice and this was associated with an even shorter lifespan (LD50=88.5 vs 33 days). Further, Crebbp or Brca1 heterozygosity influenced the hematopoietic phenotype associated with complete deficiency of Brca1 or Crebbp, respectively. We also observed lower BRCA1 protein levels in hematopoietic tissues when CREBBP is absent. Collectively, these data suggest Crebbp and Brca1 functionally interact to maintain normal hematopoiesis.